1. Technical Field
The present invention relates to certain derivatives of diimidestatin (mitindomide) which is a photosynthetic addition product of benzene and maleimide. More particularly, the present invention relates to N-methyl derivatives of diimidestatin and methods of preparing the same.
1. Description of the Prior Art
The photo-addition product of benzene and maleimide (hereinafter "mitindomide" NSC 284,356), has been reported to show strong inhibitory activity against certain experimental tumor systems [Pettit et al, Can. J. Chem. 61, 2291-2294, (1983)]. However, mitindomide is virtually insoluble in water. Therefore, such solvents as dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF) or highly alkaline media and the like are employed to solubilize mitindomide. Of course, the use of organic solvents such as DMF and DMSO and aqueous media of high pH are hazardous to human health and toxic to mammalian tissues. Clearly these solubility characteristics of mitindomide severely restrict the utility of this compound where solubility in water or in neutral or mild aqueous media is desired. The applicants have now discovered that if certain derivatives of mitindomide are prepared in accordance with the present invention, the solubility of mitindomide, particularly in water, is substantially increased. Such increased water solubility of mitindomide derivatives allows their utilization, inter alia, in water soluble form which heretofore was not possible. An example of such utility is intraperitoneal or subcutaneous administration of mitindomide derivative as an antineoplastic agent in mammalian host. Other utility of these derivative compounds will be suggested to those skilled in the art.
Certain photoaddition products of benzene with N-phenylmaleimides substituted with electron-attracting groups have been reported by Kardush et al (Chem. Abstr. 79, 125535r). Arkhipova et al (Chem. Abstr. 77, 100908K) have described the synthesis and the properties of a photoadduct of maleimide with benzene. Bryce-Smith et al, [J. Chem. Soc. (C) 390, (1967)], have described the stereochemistry of photoaddition of maleic anhydride to benzene. It is noted, however, that these references have little relevance to the present invention because they simply fail to teach or suggest the derivative compounds or mitindomide such as disclosed by the present invention.